Enkephalins, Tyr-Gly-Gly-Phe-Met(Leu), are endogenous ligands of opioid receptors μ and δ and are involved in the regulation of nociceptive impulses in the central and peripheral nervous systems. However, administered intracerebroventricularly in rodents, these peptides induce only a very brief analgesic response due to their very rapid inactivation in vivo, including in man (Mosnaim et al. (2008) Neurochem. Res., 33, 81-86), although their affinity for opioid receptors is similar to that of morphine. Two metallopeptidases are responsible for this inactivation: aminopeptidase N (APN, EC 3.4.11.2) and neprilysin (NEP, EC 3.4.24.11), which cleave, respectively, the Tyr1-Gly2 bond and the Gly3-Phe4 bond of enkephalins, thus resulting in inactive metabolites (Roques et al. (1993) Pharmacol. Rev., 45, 87-146).
Mixed inhibitors of these two enzymes are known, which by completely protecting endogenous enkephalins from their enzymatic degradation show the pharmacological activities, in particular the analgesic and antidepressant activities, of enkephalins (Noble et al. (2007) Expert. Opin. Ther. Targets, 11, 145-149). These inhibitors, disclosed in the prior art, include hydroxamates (FR2518088 and FR2605004), aminophosphinic compounds (FR2755135, FR2777780, FR0855015), amino acid derivatives with a thiol functional group (FR2651229, FR0510862, FR0604030, FR0853092), endogenous peptides (Wisner et al. PNAS (2006), 103, 17979-17984). These various molecules have physicochemical properties (solubility) and pharmacodynamic properties (bioavailability) that bestow upon them pharmacological effectiveness, intravenously or orally, on different types of pain, in particular acute or chronic pain with excess nociception (Noble et al. (2007) Expert. Opin. Ther. Targets, 11, 145-149) and neuropathic pain (Menendez et al. (2008) Eur J Pharmacol, 596, 50-55; Thibault et al. (2008) Eur. J. Pharmacol., 600, 71-77). However, none of the mixed inhibitors disclosed to date makes it possible to obtain an analgesic response that is rapid, intense and with a sufficiently long duration of action in the case of sharp pain (post-operative, cancer, traumatic, dental, etc.) after intravenous administration, at low doses enabling use in extended perfusion in a clinically suitable vehicle.
The objective of the invention is to provide compounds having the beneficial properties of morphine substances on the central nervous system, in particular analgesia, behavioral effects (reduction in the emotional component of pain and antidepressant responses) without their major disadvantages for the central nervous system (habituation, physical and psychic dependence, respiratory depression) and the peripheral nervous system (constipation). In addition, it will be advantageous that the compounds have beneficial peripheral effects (anti-inflammatory and anti-neuropathic) without the disadvantages stated above.